Phosphonosuccinic acid derivatives, processes for their preparation and medicaments containing these compounds

ABSTRACT

Compounds of the formula (I) in which: R is a possibly substituted amino group of the general form --NR 1  R 2 , in which R 1  and R 2  are independently hydrogen, lower alkyl, lower alkenyl or lower alkinyl, or R is a saturated, unsaturated or aromatic heterocyclic ring which may be mono or bi-substituted by lower alkyl or halogen; alk is a valency bond, a methylene, a saturated or unsaturated, straight or branched-chain alkylene chain with 2-6 carbon atoms; and R 3 , R 4 , R 5  are independently hydrogen, lower alkyl or benzyl; and their pharmacologically acceptable salts and enantiomers where, if R 3  ═R 4  ═R 5  ═CH 3  and alk is a valency bond, R may not be the dimethyl amino group. Process for their production and medicaments containing these compounds, for the treatment of calcium metabolic complaints.

The present invention concerns new phosphonosuccinic acid derivatives,processes for their operation, as well as medicaments which containthese substances.

In Phosphorus and Sulphur 13, 85 (1982) is described the synthesis of3-dimethylamino-2-dimethylphosphonosuccinic acid dimethyl ester but apharmacological action of this compound is not known.

It has now been found that analogous phosphonosuccinic acid derivativesdisplay an excellent action on the calcium metabolism and thus aresuitable for the broad treatment of calcium metabolism disturbances. Inparticular, they can be very well used there where the bone build up andbreakdown is disturbed, i.e. they are suitable for the treatment ofdiseases of the skeletal system, such as e.g. osteoporosis, Paget'sdisease, Bechterev's disease and the like.

However, on the basis of these properties, they can also find use forthe therapy of urolithiasis and for the prevention of heterotopicossifications. Furthermore, due to their influencing of the calciummetabolism, they also form a basis for the treatment of rheumatoidarthritis, of osteoarthritis and of degenerative arthrosis.

The subject of the present invention are compounds of the generalformula I, ##STR2## in which R signifies a possibly substituted aminogroup of the general formula --NR¹ R², whereby, independently of oneanother, R¹ and R² each signify hydrogen, lower alkyl, lower alkenyl orlower alkynyl or R represents a saturated, unsaturated or aromaticheterocyclic ring which can possibly be substituted once or twice bylower alkyl or halogen, alk signifies a valency bond, a methylene, asaturated or unsaturated, straight-chained or branched alkylene chainwith 2-6 carbon atom and R³, R⁴, R⁵, in each case independently of oneanother, signify hydrogen, lower alkyl or benzyl, as well as theirpharmacologically acceptably salts, whereby, for the case that R³ ═R⁴═R⁵ ═CH₃ and alk signifies a valency bond, R cannot be the dimethylaminogroup.

In all cases, lower alkyl is to represent a straight-chained or branched₁ -C₆ -alkyl group, such as e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl or hexyl radical, especially methyl, ethyl,propyl, isobutyl or pentyl.

Lower alkenyl signifies unsaturated radicals with 3-6 carbon atoms, suchas e.g. allyl, but 2-enyl, hexa-2,4-dienyl, above all allyl.

Lower alkynyl is to represent unsaturated radicals with 3-6 carbonatoms, such as e.g. propargyl, but-3-ynyl, hex-5-ynyl but especiallypropargyl.

If the radical R signifies a saturated heterocyclic ring, it is aquestion of 3-8 membered rings which can also contain one or two furtherheteroactoms, such as the aziridine, azetidine, pyrrolidine, piperidine,azepine, morpholine or the thiomorpholine ring, especially thepyrrolidine, azepine and the morpholine ring.

If R signifies an unsaturated heterocyclic ring, as a rule it is aquestion of the imidazoline ring.

If R represents a hetero-aromatic ring, it is a question of a five- orsix-membered ring, such as the pyridine, pyrimidine, pyrazine,imidazole, especially the pyridine and imidazole ring.

The heterocyclic rings can possibly by substituted once or twice by C₁-C₆ -alkyl groups, preferably the methyl, ethyl or isopropyl group, aswell as by chlorine or bromine.

In the case of the saturated or unsaturated, straight-chained orbranched alkylene chains, alk represents radicals such as e.g.methylene, ethylene, propylene, butylene, 2-methylpropylene, pentylene,1,1-dimethylpropylene, 2,3-dimethylpropylene, 2,2-dimethylpropylene,2-methylbutylene, hexylene, 2,3-dimethylbutylene, 2-methylpentylene,2-butenylene, 2-butynylene, especially methylene, ethylene, propylene,butylene, 2-methylpropylene, pentylene, hexylene and 2-butenylene.

Compounds of general formula I contain at least two assymmetric carbonatoms, therefore optically-active compounds of the general formula I arealso the subject of the present invention.

Compounds of general formula I are prepared according to per se knownprocesses, preferably in that one

a) reacts carboxylic acid derivatives of the general formula II ##STR3##in which R, alk and R⁴ have the above-given meanings and Y signifies agroup which can be removed, such as e.g. Hal or O--SO₂ --Z, whereby Halis to be chloride, bromide or iodide and Z methyl, phenyl,p-methylphenyl or p-nitrophenyl, with a phosphonoacetic acid ester ofthe general formula III ##STR4## in which R³ and R⁵ possess theabove-given meanings, whereby, for the case that R signifies a primaryor secondary amino group, this must be present in protected form,perhaps as acylamino or phthaloylimido group, and possibly saponifiesthe resultant ester partly or completely to the corresponding acids ofthe general formula I, or

b) reacts compounds of the general formula IV ##STR5## in which R, alk,R³ and R⁴ have the above-given meanings, with a dialkyl phosphite of thegeneral formula V

    H--P(O)(OR.sup.5).sub.2                                    (V)

in which R⁵ has the above-given meanings, and possibly saponifies theresultant ester partly or completely to the corresponding acids of thegeneral formula I, or

c) brings a compound of the general formula VI or VII ##STR6## in whichR³, R⁴ and R⁵ possess the above-given meanings, to reaction is per seknown manner with a compound of the general formula VIII

    R--alk-M                                                   (VIII)

in which R possesses the above-given meanings and M signifies hydrogenor an alkali metal or alkaline earth metal, and possibly saponifies theresultant ester partly or completely to the corresponding acids of thegeneral formula I and, if desired, converts into pharmacologicallyacceptably salts.

Compounds of the general formula II are so prepared that, for the casethat Y=Hal, one halogenates a compound of the general formula IX

    R-alk--CH.sub.2 --CO.sub.2 R.sup.4                         (IX)

in which R, alk and R⁴ possess the above-given meanings, according toprocesses known from the literature or, for the case that Y in formulaII signifies the O--SO₂ --Z group, converts the hydroxyl group of acompound of general formula (X) ##STR7## in which R, alk and R⁴ possessthe above-given meanings, into the corresponding sulphonic acid ester.

Some of the compounds of the general formula III are commerciallyavailable (Aldrich-Chemie GmbH & Co, KG) and, in special cases, areprepared by reaction of a haloacetic acid derivative of the generalformula XI

    Hal--CH.sub.2 --CO.sub.2 R.sup.3                           (XI)

in which Hal and R³ possess the above-given meanings, with atriphosphite of the general formula XII

    P(OR.sup.5).sub.3                                          (XII)

in which R⁵ possesses the above-given meaning.

Compounds of the general formula IV are prepared in that one

1. alkylates a compound of the general formula XIII

    R--H                                                       (XIII)

in which R possesses the above-given meaning, with a compound of thegeneral formula XIV ##STR8## in which Hal, alk, R³ and R⁴ possess theabove-given meanings, or

2. dehydrates according to known processes a compound of the generalformula XV ##STR9## in which R, alk, R³ and R⁴ possess the above-givenmeanings.

Compounds of general formula C are commercially available (Aldrich Co.).

Compounds of general formula VI are prepared in that one brings toreaction a compound of general formula V with an acetylene-dicarboxylicacid ester of the general formula XVI

    R.sup.4 O.sub.2 C--C--C--CO.sub.2 R.sup.3                  (XVI)

in which R³ and R⁴ have the above-given meaning.

Compounds of general formula VII are prepared in per se known manner inthat one reacts a compound of the general formula XVII, ##STR10## inwhich R³ and R⁴ possess the above-given meanings, with a compound of thegeneral formula XII.

For the case that M does not signify hydrogen, compounds of the generalformula VIII are metallised by processes according to the literature.

Compounds of the general formula IX are obtained according to knownprocesses by alkylation of a compound of the general formula XIII with acompound of the general formula XVIII

    Hal--alk--CH--.sub.2 --CO.sub.2 R.sup.4                    (XVIII)

in which Hal, alk and R⁴ possess the above-given meanings.

Compounds of the general formula X can be obtained by processes knownfrom the literature by oxidation of the corresponding compounds of thegeneral formula IX.

Compounds of the general formula XIV can be prepared in per se knownmanner in that one reacts a compound of the general formula XIX##STR11## in which R³ and R⁴ possess the above-given meanings, with acompound of the general formula XX

    Hal--alk--Hal                                              (XX)

in which Hal and alk have the above-given meanings.

Compounds of the general formula XV are prepared in per se known mannerby reaction of a compound of the general formula IX with a compound ofthe general formula XXI ##STR12## in which R³ possesses the above-givenmeanings.

One obtains compounds of the general formula XVII according to knownmethods by allylic bromination of a compound of the general formula XXII##STR13## in which R³ and R⁴ possess the above-given meanings.

The halogenation of a compound of the general formula IX takes place byits reaction with molecular halogen (chlorine, bromine, iodine),preferably bromine, without solvent or in an inert solvent, such asmethylene chloride, chloroform or carbon tetrachloride, preferablycarbon tetrachloride, and with addition of red phosphorus, phosphorustrichloride or phosphorus tribromide and at a temperature between roomtemperature and 100° C., preferably at 90° C. (K. Stoh, Chem. Pharm.Bull., 34, 2078 (1986); H. J. Ziegler, Synthesis, 1969, 39).Furthermore, compounds of the general formula IX can be halogenated inthat metallises them in an aprotic solvent, such as tetrahydrofuran, andat low temperature, preferably at -78° C., with a lithium amide, such aslithium diisopropylamide, and subsequently reacts the compoundsmetallised in that -position of the general formula IX with bromine,iodine, carbon tetrachloride or carbon tetrabromide (M. Hesse, Helv.Chim, Acts 72, 847 (1989); R. T. Arnold, J. Org. Chem. 43, 2687 (1978)or with N-chloro- or N-bromosuccinimide (W. Oppolzer, Tetrahedron Lett.26, 5037 (1985)).

The conversion of the hydroxyl group of a compound of the generalformula X into a sulphonic acid ester group takes place according toconventional processes, such as e.g. by the condensation with asulphonic acid chloride, such as methane-, benzene-, p-toluene- orp-nitrobenzenesulphonic acid chloride, in an inert solvent, such asmethylene chloride, tetrahydrofuran or diethyl ether, preferablymethylene chloride, with the use of an adjuvant base, such as trimethyl-or triethylamine or pyridien, preferably triethylamine, and at atemperature between 0° C. and room temperature.

For the preparation of compounds of the general formula XIX, see R.Eyjolfsson, Acta. Chem. Scand., 3075 (1970).

The reaction of a compound of the general formula II with a compound ofthe general formula III takes place, as a rule, in an aprotic solvent,such as toluene, tetrahydrofuran, diethyl ether or dimethylformamide,preferably dimethylformamide or tetrahydrofuran, with the use of astrong base, such as potassium hydride, sodium hydride, lithiumdiisopropylamide or lithium hexaneethyl disilylamide, preferably sodiumhydride or lithium diisopropylamide, and at temperatures between -78° C.and 90° C. but preferably between -10° C. and room temperature.

The reaction of a compound of the general formula IV with a compound ofthe general formula V takes place under the conditions of the Michaeladdition in a solvent, such as methanol, ethanol, toluene,tetrahydrofuran, diethyl ether or dimethylformamide, preferablymethanol, tetrahydrofuran or dimethylformamide, without furtheradditions or with use of a base, such as sodium or potassium methylateor ethylate, sodium hydride, potassium hydride or lithiumdiisopropylamide, preferably sodium methylate, sodium hydride or lithiumdiisopropylamide, and at temperatures between -78° C. and 90° C. andpreferably between -10° C. and room temperature.

As a rule, one carries out the reaction between a compound of thegeneral formula VI or VII with a compound of the general formula VIIIunder the conditions of the Michael addition in a solvent, such asmethanol, ethanol, toluene, tetrahydrofuran, diethyl ether ordimethylformamide, preferably methanol, tetrahydrofuran ordimethylformamide, without further additives or with use of a base, suchas sodium hydride, potassium hydride, lithium diisopropylamide, butyllithium, ethyl magnesium bromide, and possibly copper slat, such ascopper chloride or bromide, for the formation of the correspondingcuprate of a compound of the general formula VIII (cf. G. H. Posner,Tetrahedron Letters, 37, 3215 (1977)) and at temperatures between -78°C. and 90° C., preferably between -78° C. and room temperature.

The reaction between a compound of the general formula XI with acompound of the general formula XII takes place, as a rule, withoutsolvent at temperatures between room temperature and 150° C. preferablyat 130° C. with a reaction time between 30 min and 30 hours, preferably18 hours.

As a rule, one carries out the alkylation of a compound of the generalformula XIII with a compound of the general formula XIV or of a compoundof the general formula XVIII in a solvent, such as methanol, ethanol,propanol, tetrahydrofuran, diethyl ether or dimethylformamide,preferably methanol, tetrahydrofuran or dimethylformamide, with adjuvantbases or with addition of a base, such as potassium carbonate, sodiummethylate, sodium or potassium hydride, lithium diisopropylamide, butyllithium or phenyl lithium, preferably sodium hydride, potassiumcarbonate, butyl lithium or phenyl lithium, and at a temperature between-78° C. and the reflux temperature of the solvent used, preferablybetween -78° C. and 50° C. The dehydration of a compound of the generalformula XV usually takes place in a solvent, such as benzen, toluene,xylene, chloroform or methylene chloride, preferably toluene ormethylene chloride, with addition of dehydration agent, such assulphuric acid, phosphoric acid, p-toluenesulphonic acid, preferablyp-toluenesulphonic acid, and at a temperature between room temperatureand reflux temperature of the solvent used, preferably at 100° C. forthe reaction of a compound V with a compound XVI, see R. Burgada,Phosphorus and Sulfur, 13, 85 (1982).

The reaction of a compound XII with a compound XVII takes place, as arule, without a solvent at temperatures between 50° C. and 180° C.,preferably at 150° C.

as a rule, one carries out the reaction of a compound of the formula XIXwith a compound of the formula XX in an inert solvent, such astetrahydrofuran, with use of a base, such as lithium diisopropylamide,and at a temperature of -78° C. (M. P. Cooke, Tetrahedron Lett., 22, 381(1981)).

One usually carries out the condensation of a carboxylic acid ester ofthe general formula IX with an aldehyde of the formula XXI in a solvent,such as methanol, ethanol, tetrahydrofuran, diethyl ether ordimethylformamide, preferably in methanol or tetrahydrofuran, in thepresence of a basic condensation agent, such as sodium methylate orethylate, potassium tert.-butylate, sodium hydride or lithiumdiisopropylamide, preferably sodium methylate, potassium tert.-butylateor lithium diisopropylamide, and at temperature between -78° C. and 60°C., preferably between -78° C. and room temperature.

For the allylic bromination of 2-methylfumaric or malic acid and theirderivatives see J. Org. Chem. 34, 1228 (1969). As a rule, one carries atthe oxidation of a compound of the general formula IX to give a compoundof the general formula X in a solvent, such as tetrahydrofuran, byaddition of a base, such as lithium diisopropylamide or lithiumN-isopropyl-N-cyclohexylamide, with the use of an oxidation agent, suchas an oxaziridine derivative, molybdenum peroxide or atmospheric oxygen,and at temperatures between -78° C. and room temperature, preferably at50° C. (C. Tamm, Tetrahedron Lett., 26, 203 (1985); F. A. Davis, J. Org.Chem. 51, 2402 (1986); C. Winotai, Synth. Commun. 18, 2141 (1988)).

The free phosphonic acid group in compounds of the general formula I canbe converted by heating with orthoformic acid trialkyl esters into thecorresponding dialkyl esters. The hydrolysis of a phosphonic acid estergroup in compounds of the general formula I to the corresponding freephosphonic acid group takes place, as a rule, without solvents or in aninert solvent, such as methylene chloride, by means of a trimethylsilylhalide, such as trimethylsilyl bromide or iodide, and at a temperaturebetween -50° C. and room temperature, preferably at 0° C.

The esterification of the free carboxylic acid groups in compounds ofthe general formula I takes place according to processes known from theliterature by heating of a compound of the general formula I, in whichR³ and/or R⁴ signifies hydrogen, with an alcohol contained in thecarboxylic acid ester to be prepared, with addition of an acidiccatalyst, such as hydrochloric acid, sulphuric acid orp-toluenesulphonic acid, preferably sulphuric acid. One carries out thesaponification of a carboxylic acid ester group in compounds of thegeneral formula I according to conventional processes in that one treatsa carboxylic acid ester of the general formula I in water or in mixturesor ethanol, preferably in a water/tetrahydrofuran mixture, with ahydroxide, such as sodium, potassium or lithium hydroxide, preferablysodium or lithium hydroxide, and at temperatures between roomtemperature and 80° C., preferably at room temperature.

The protective group of a primary or secondary amino group in compoundsof the general formula I can be removed in that, according toconventional processes, one treats a compound of the general formula I,in which R signifies an acylamino or phthaloylimido group, with aqueousmineral acids or bases, such as hydrochloric acid or sulphuric acid orcaustic soda or caustic potash solution, or reacts it with hydrazine orhyroxylamine.

Furthermore, phosphonic and carboxylic acid ester groups in compounds ofthe general formula I can be saponified by boiling with hydrochloric orhydrobromic acid. If benzyl esters are present in the compounds of thegeneral formula I, then they can be converted hydrogenolytically intothe corresponding free phosphonic or carboxylic acids.

As pharmacologically acceptable salts, there are, above all, used mono-or dialkali metal or ammonium salts which one prepares in the usual way,e.g. by titration of the compounds with inorganic or organic bases, suchas e.g. sodium or potassium hydrogen carbonate, caustic soda solution,caustic potash solution, aqueous ammonia or amines, such as e.g.trimethyl- or triethylamine.

As a rule, the salts are purified by reprecipitation from water/acetone.

The new substances of the formula I according to the invention and theirsalts can be administered enterally or parenterally in liquid or solidform. All conventional forms of administration hereby come intoquestion, for example tablets, capsules, dragees, syrups, solutions,suspension etc. As injection medium, water is preferably used whichcontains the additives usual in the case of injection solutions, such asstabilising agents, solubilising agents and buffers.

Such additives are e.g. tartrate and citrate buffers, ethanol, complexformers (such as ethylenediamine-tetraacetic acid and its non-toxicsalts), high molecular polymers (such as liquid poly;ethylene oxide) forviscosity regulation. Liquid carrier materials for injection solutionsmust be sterile and are preferably filled into ampoules. Solid carriermaterials are e.g. starch, lactose, mannitol, methyl cellulose, talc,highly dispersed silicic acids, high molecular fatty acids (such asstearic acid), gelatine, agar-agar, calcium phosphate, magnesiumstearate, animal and vegetable fats, solid high molecular polymers (suchas polyethylene glycols); compositions suitable for oral administrationcan, if desired, contain flavouring and sweetening materials.

The dosaging can depend upon various factors, such as manner ofadministration, species, age and/or individual state of health. Thedoses to be administered daily lie at about 10-1000 mg/human, preferably100-500 mg/human and can be taken all at once or divided up severaltimes.

Preferred in the meaning of the present invention are, apart from thecompounds mentioned in the Examples and compounds derivable bycombination of all of the meanings of the substituents mentioned in theclaims, the following succinic acid derivatives, as well as their sodiumand potassium salts, methyl, ethyl or bencyl esters:

a) 3-amino-2-phosphonosuccinic acid; m.p. 220° C. (decomp.)

b) 3-dimethylamino2-phosphonosuccinic acid

c) 3-(N-methyl-N-propylamino)-2-phosphonosuccinic acid

d) 3-(1-pyrrolidino)-2-phosphonosuccinic acid

e) 3-(imidazol-1-yl)-2-phosphonosuccinic acid

f) 3-aminomethyl-2-phosphonosuccinic acid; m.p. 103° C. (decomp.)

g) 3-dimethylaminomethyl-2-phosphonosuccinic acid; m.p. 112° C.(decomp.)

h) 3-(N-methyl-N-pentylamino)-methyl-2-phosphonosuccinic acid; m.p. 110°C.

i) 3-(2-dimethylaminoethyl)-2-phosphonosuccinic acid

j) 3-{2-(N-methyl-N-propylamino)-ethyl}-2-phosphonosuccinic acid

k) 2-phosphono-3-{2-(pyrrolidin-1-yl)-ethyl}-succinic acid

l) 3-{2-(imidazol-1-yl)-ethyl}-2-phosphonosuccinic acid

m) 3-(3-aminopropyl)-2-phosphonosuccinic acid; m.p. 121° C. (decomp.)

n) 2-phosphono-3-{3-(pyrrolidin-1-yl)-succinic acid

o) 3-(4-aminobutyl)-2-phosphonosuccinic acid; m.p. 135° C. (decomp.)

p)2-phosphono-3-{4-(pyrrolidin-1-yl)-butyl}-succinic acid

q) 3-(5-aminopentyl)-2-phosphonosuccinic acid

r) 2-phosphono-3-{5-(pyrrolidin-1-yl)-pentyl}-succinic acid

s) 3-{5-(imidazol-1-yl)-pentyl}-2-phosphonosuccinic acid

t) 3-(6-aminohexyl)-2-phosphonosuccinic acid

u) 2-phosphono-3-{6-(pyrrolidin-1-yl)-hexyl}-succinic acid

v) 3-{6-(imidazol-1-yl)-hexyl}-2-phosphonosuccinic acid

w) 2-phosphono-3-(pyrid-2-yl)-succinic acid

x) 2-phosphono-3-(pyrid-3-yl)-succinic acid

y) 2-phosphono-3-(pyrid-4-yl)-succinic acid

z) 3-(imidazol-2-yl)-2-phosphonosuccinic acid

aa) 3-(imidazol-4-yl)-2-phosphonosuccinic acid

ab) 2-phosphono-3-(pyrrolidin-2-yl)-succinic acid

ac) 2-phosphono-3-(pyrrolidin-3-yl)-succinic acid

ad) 2-phosphono-3-(pyrid-2-ylmethyl)-succinic acid

ae) 2-phosphono-3-(pyrid-4-ylmethyl)-succinic acid

af) 2-phosphono-3-(pyrid-4-ylmethyl)-succinic acid

ag) 3-(imidazol-2-ylmethyl)-2-phosphonosuccinic acid

ah) 3-(imidazol-4-ylmethyl)-2-phosphonosuccinic acid

ai) 2-phosphono-3-(pyrrolidin-2-ylmethyl)-succinic acid

aj) 2-phosphono-3-(pyrrolidin-3-ylmethyl)-succinic acid

ak) 2-phosphono-3-{2-(pyrid-2-yl)-ethyl}-succinic acid

al) 2-phosphono-3-{2-(pyrid-3-yl)-ethyl}-succinic acid

am) 2-phosphono-3-{2-(pyrid-4-yl)-ethyl}-succinic acid

an) 3-{2-imidazol-2-yl)-ethyl}-2-phosphonosuccinic acid

ao) 3-{2-(imidazol-4-yl)-ethyl}-2-phosphonosuccinic acid

ap) 2-phosphono-3-{2-(pyrrolidin-2-yl)-ethyl}-succinic acid

ar) 3-{3-(imidazol-4-yl)-propyl}-2-phosphonosuccinic acid

as) 2-phosphono-3-{4-(pyrrolidin-2-yl)-butyl}-succinic acid

at) 3-(N-allyl-N-methylamino)-2-phosphonosuccinic acid

au) 3-(N-methyl-N-propargylamino)-2-phosphonosuccinic acid

av) 3-{4-(N-allyl-N-propargylamino)-butyl}-2-phosphonosuccinic acid

ax) 3-{4-(n-ethyl-N-isobutylamino)-butyl}-2-phosphonosuccinic acid

ay) 3-(azepin-1-ylmethyl)-2-phosphonosuccinic acid

az) 2-phosphono-3-{1-(pyrrolidin-1-yl)ethyl}-succinic acid

ba) 2-phosphono-3-{2-(pyrid-2-yl)-propyl}-succinic acid

bb) 2-phosphono-3-{1-methyl-1-(pyrid-3yl)-ethyl}-succinic acid

bc) 3-{3-(imidazol-1-yl)-2-methylpropyl}-2-phosphonosuccinic acid

bd) 3-(3-aminobutyl)-2-phosphonosuccinic acid

be)3-{1,1-dimethyl-3-(N-methyl-N-pentylamino)-propyl}-2-phosphonosuccinicacid

bf) 3-{3-(imidazol-4-yl)-2,3-dimethylpropyl}-2-phosphonosuccinic acid

bg) 3-(2,2-dimethyl-3-dimethylaminopropyl)-2-phosphonosuccinic acid

bh) 3-{2-methyl-4-(pyrrolidin-2-yl)-butyl}-2-phosphonosuccinic acid

bi) 3-{2,3-dimethyl-4-(pyrrolidin-2-yl)-butyl}-2-phosphonosuccinic acid

bj) 3-(5-amino-2-methylpentyl)-2-phosphonosuccinic acid

bk) 2-phosphono-3-{4-(pyrid-2-yl)-but-2-enyl}-succinic acid

bl) 2-phosphono-3-{4-pyrid-4-yl)-but-2-ynyl}-succinic acid

The following Examples show some of the process variants which can beused for the synthesis of the compounds according to the invention.However, they do not represent a limitation of the subject matter of theinvention. The structure of the compounds was verified by ¹ H-, ³¹ P-and possibly by ¹³ C-NMR spectroscopy. The purity of the compounds wasdetermined by means of C, H, N, P, possibly Na analysis, as well as thinlayer chromatographically or by thin layer electrophoresis (cellulose,oxalate buffer of pH=4.0).

EXAMPLE 1 2-Diethylphosphono-3-methoxycarbonyl-5-phthaloylimidovalericacid ethyl ester

To 240 mg (10 mmol) sodium hydride in 10 ml absolute toluene one addsdropwise, with cooling, 2.24 g (10 mmol) phosphonoacetic acid triethylester. After ending of the evolution of hydrogen, one adds dropwise asolution of 3.26 g (10 mmol) 2-bromo-4-phthaloylimidobutyric acid methylester (Hoppe-Seyler Z. Physiol. Chem. 1967, 160) in 70 ml absolutetoluene and allows to stir for 24 hours at room temperature. Thesolution is neutralised with about 1 ml ethereal hydrochloric acid,evaporated on a rotary evaporator and the remaining oil purified over200 g of silica gel (elution agent: acetone/toluene 1:1 v/v). Oneobtains 2.8 g=60% of a colourless oil, the structure of which wasverified by NMR spectroscopy.

EXAMPLE 2 3-(2-Aminoethyl)-2-phosphonosuccinic acid

1.5 g (3.2 mmol) of the tetraester described in Example 1 are heatedunder reflux for 8 hours in 40 ml 6N hydrochloric acid. The solution isconcentrated to about 10 ml, the resultant precipitate filtered off withsuction, the filtrate completely evaporated, the residue stirred with 3ml of water, filtered off with suction and the filtrate againevaporated. One obtains a brownish oil which is dissolved in 2 ml ofwater and passed over 25 g of ion exchanger (Amberlite IR 120; H⁺ form).The column is eluted with water and the fractions with the desiredsubstance evaporated. One obtains 0.34 g=40% of a white, amorphouspowder with the m.p.: 127°-130° C. with decomposition.

EXAMPLE 32-Diethylphosphono-3-ethoxycarbonyl-7-(imidazol-1-yl)-heptane-carboxylicacid ethyl ester

To 48 g (2 mmol) sodium hydride in 2 ml absolute toluene one addsdropwise 552 mg (4 mmol) diethyl phosphite and, after a further 5minutes, a solution of 588 mg (2 mmol) 4-(imidazol-1-yl)-butylfumaricacid diethyl ester in 4 ml absolute toluene. After 20 hours, oneneutralises with ethereal hydrochloric acids, strips off the solvent andpurifies the oily residue over 200 g of silica gel (elution agent:acetone/toluene 1:1 v/v). One obtains 380 mg=44% of a yellowish oil.

One obtains the 4-(imidazol-1-yl)-butylfumaric acid diethyl ester usedas starting material in the following way:

To 72 mg (3 mmol) sodium hydride in 3 ml absolute dimethylformamide oneadds 204 mg (3 mmol) imidazole. After 15 minutes, one adds to the clearyellowish solution 921 mg (3 mmol) (4-bromobutyl)-fumaric acid diethylester (Tetrahedron Letters, 22, 381 (1981)). One allows to stirovernight, neutralises with ethereal hydrochloric acid, evaporates andpurifies the remaining oil over 150 g of silica gel (elution agent:acetone/toluene 1:1 v/v). One obtains 750 mg=41% of the desiredsubstance as oil.

EXAMPLE 4 3-{4-(Imidazol-1-yl)-butyl}-2-phosphonosuccinic acid

432 mg (1 mmol) of the tetraester described in Example 3 are heatedunder reflux for 6 hours in 15 ml 6N hydrochloric acid. The solution isthen evaporated, the residue dissolved in 2 ml of water and passed over20 g of ion exchanger (Amberlite IR 120; H⁺ form). The column is elutedwith water and the fractions with the desired substance evaporated. Oneobtains 165 mg=52% of a white, amorphous powder with an m.p.: 161°-164°C. with decomposition.

EXAMPLE 52-Diethylphosphono-3-methoxycarbonyl-4-(pyrrolidin-1-yl)-butyric acidmethyl ester

To 1.1 g (3.74 mmol) 2-diethylphosphono-3-methoxycarbonylbut-3-enoicacid methyl ester in 10 ml absolute toluene one adds 265 mg (3174 mmol)freshly distilled pyrrolidine. One leaves the solution to stand for 24hours at room temperature, evaporates and purifies over 100 g of silicagel (elution agent: acetone/toluene 1:4 v/v). One obtains 490 mg=38% ofthe desired substance as oil. The NMR spectrum confirms the structure.

One prepares the 2-diethylphosphono-3-methoxycarbonylbut-3-enoic acidmethyl ester used as starting material in the following way:

To 7.19 g (30 mmol) 2-bromoethylfumaric acid dimethyl ester (J. Org.Chem., 34, 1228 (1969) one slowly adds dropwise 5.2 ml (3) mmol)triethyl phosphite. The internal temperature thereby increases to 90° C.One then heats for 1 hour to 150° C., allows to cool and purifies theoil over a silica gel column (elution agent: acetone/toluene 1:4 v/v).One obtains 4.9 g=54% of the desired compound as oil. The structure wasconfirmed by NMR and mass spectroscopy.

EXAMPLE 6 2-Phosphono-3-(pyrrolidin-1-ylmethyl)-succinic acid

3.65 g (10 mmol) of the tetraester described in Example 5 are heatedunder reflux for 6 hours in 50 ml 6N hydrochloric acid. The solution isthen evaporated, the residue dissolved in 20 ml of water and purifiedover an ion exchanger (Amberlite IR 120; H⁺ form). The fractions withthe desired substance are evaporated and dried. One obtains 2.14 g=74%of a white powder with 0.5 mol water of crystallisation; m.p. 122°-124°C. with decomposition.

EXAMPLE 7 2-Diethylphosphono-4-(imidazol-1-yl)-3-methoxycarbonylbutyricacid methyl ester

To 75 mg (3 mmol) sodium hydride in 10 ml absolute toluene one addsdropwise 205 mg (3 mmol) imidazole in 10 ml absolute tetrahydrofuran.After ending of the hydrogen evolution, one adds thereto 1.18 g (4 mmol)2-diethylphosphono-3-methoxycarbonylbut-3-enoic acid methyl ester (seeExample 5) in 20 ml absolute tetrahydrofuran and leaves to stir for 72hours. One evaporates the mixture, adds thereto 20 ml of water, adjuststhe pH=6 with 2N hydrochloric acid and extracts several times withmethylene chloride. The combined organic phases are dried andevaporated. The residue is purified over 100 g of silica gel (elutionagent: acetone/toluene 3:1 v/v). One obtains 610 mg=61% of the desiredsubstance as oil. The NMR spectrum confirms the structure.

EXAMPLE 8 3-(Imidazol-1-ylmethyl)-2-phosphonosuccinic acid

1.08 g (3 mmol) of the tetraester described in Example 7 are heatedunder reflux for 6 hours with 30 ml 6N hydrochloric acid. One thanevaporates the solution, takes up the residue in a little water, bringsthe solution to a pH=5 with 2N caustic soda solution, mixes it with thethreefold volume of methanol and leaves to stand in a refrigerator. Theprecipitate formed is filtered off with suction, washed with methanoland dried. One obtains 487 mg=47% of white powder as disodium salt with2 mol water of crystallisation; m.p. 135°-137° C. with decomposition.

Pharmacological Comparative Experiment EXAMPLE 9 Osteoclast Assay

Material and method:

The carrying out of the experiment took place according to the method ofP. Collin, H. Gunther and H. Fleisch (endocrinol. 131, 1181-76, 1982)with the use of freshly isolated osteoclasts.

Special feature:

The osteoclast preparation suspended in the Medium 199 (Gibco AG, Basel,Switzerland) at pH 7.36 is treated 5 minutes before and for 25 minutesduring the adhesion to wall dentine, as well as during the 24 hoursassay time (in MEM Earle's), with 10⁻⁸ M of substance.

The calculation of the action (% resorption inhibition) took place inthis assay according to the following formula:

    ______________________________________                                         ##STR14##                                                                                                 resorption                                       Example No.                                                                              systematic name   inhibition                                       ______________________________________                                        2          3-(2-aminoethyl)-2-phos-                                                                        80%                                                         phonosuccinic acid                                                 6          2-phosphono-3-(pyrrolidin-                                                                      71%                                                         1-ylmethyl)-succinic acid                                          8          3-(imidazol-1-ylmethyl)-                                                                        73%                                                         2-phosphonosuccinic acid                                           .sup. g)   3-dimethylaminomethyl-                                                                          60%                                                         2-phosphonosuccinic acid                                           .sup. a)   3-amino-2-phosphono-                                                                            59%                                                         succinic acid                                                      .sup. h)   3-(N-methyl-N-pentyl-                                                                           51%                                                         amino)-methyl-2-phosphono-                                                    succinic acid                                                      ______________________________________                                    

We claim:
 1. A phosphonosuccinic acid derivative of the formula ##STR15## where: R is an amino group of the formula --NR₁ R₂, wherein R₁ and R₂ are independently hydrogen, C₁ -C₆ -alkyl, C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl;alk is a valency bond, methylene or a saturated or unsaturated, straight-chained or branched alkylene chain or 2-6 carbon atoms; and R₃, R₄ and R₅ are independently hydrogen; or a pharmacologically acceptable salt or enantiomer thereof.
 2. Compound of claim 1, wherein alk is methylene, ethylene, propylene, butylene, pentylene, 2-methylpropylene, hexylene or 2-butenylene.
 3. The compound of claim 1 wherein the compound is 3-(2-aminoethyl)-2-phosphonosuccinic acid.
 4. A pharmaceutical composition suitable for the treatment of calcium metabolism disturbances comprising a compound of the formula ##STR16## where: R is an amino group of the formula --NR₁ R₂, wherein R₁ and R₂ are independently hydrogen, C₁ -C₆ -alkyl, C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl;alk is a valency bond, methylene or a saturated or unsaturated, straight-chained or branched alkylene chain of 2-6 carbon atoms; and R₃, R₄ and R₅ are independently hydrogen; or a pharmacologically acceptable salt or enantiomer thereof and a pharmaceutically acceptable carrier therefor.
 5. A method of treatment of a calcium metabolism disturbance in a patient in need of such treatment, said method comprising administering to said patient a calcium metabolism disturbance treating amount of a compound of the formula ##STR17## where: R is an amino group of the formula --NR₁ R₂, wherein R₁ and R₂ are independently hydrogen, C₁ -C₆ -alkyl, C₃ -C₆ -alkenyl or C₃ -C₆ -alkynyl;alk is a valency bond, methylene or a saturated or unsaturated, straight-chained or branched alkylene chain of 2-6 carbon atoms; and R₃, R₄ and R₅ are independently hydrogen; or a pharmacologically acceptable salt or enantiomer thereof. 